Recruitment of TBK1/IKK epsilon to K63-pUb-TANK:K63-pUb-TRAF3:TRIF:activated TLR4 followed by their phosphorylation

Stable Identifier
R-HSA-936941
Type
Reaction [binding]
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
General
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

Upon stimulation by pathogen-associated inflammatory signals, TANK-binding kinase 1 (TBK1) and inhibitor of ?B kinase epsilon (IKKi) induce type I interferon expression and modulate nuclear factor ?B (NFkB) signaling (Fitzgerald KA et al. 2003; Hemmi H et al. 2004). The structural studies of TBK1 revealed a dimeric assembly which is mediated by several interfaces involving kinase domain (KD), a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 (Larabi A et al. 2013; Tu D et al. 2013). ULD of TBK1 and IKKi was involved in the control of kinase activation, substrate presentation and downstream signaling (Ikeda F et al 2007; Tu D et al. 2013). An intact TBK1 dimer was a subject to K63-linked polyubiquitination on lysines 30 and 401 (Tu D et al. 2013). Activation of TBK1 rearranged the KD into an active conformation while maintaining the overall dimer conformation (Larabi A et al. 2013). The ubiquitination sites and dimer contacts are conserved in the close homolog IKKi (Tu D et al. 2013). The activation of TBK1 and IKKi may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al. 2009). Other studies demonstrated an essential role of TRAF3 in the activation of TBK1 (Hacker et al 2006). TBK1 and IKKi were found to interact with scaffold proteins TANK (TRAF family member associated NFkB activator), NAP1 (NAK-associated protein 1), SINTBAD (similar to NAP1 TBK1 adaptor) which connect TBK1/IKKi to pathogen-activated signaling cascades (Pomerantz JL and Baltimore D 1999; Guo B and Cheng G 2007; Gatot JC et al. 2007; Ryzhakov G and Randow F 2007; Goncalves A et al. 2011).

Literature References
PubMed ID Title Journal Year
17047224 Regulation and function of IKK and IKK-related kinases

Hacker, H, Karin, M

Sci STKE 2006
15210742 The roles of two IkappaB kinase-related kinases in lipopolysaccharide and

Hemmi, H, Takeuchi, O, Sato, S, Yamamoto, M, Kaisho, T, Sanjo, H, Kawai, T, Hoshino, K, Takeda, K

J Exp Med 2004
12692549 IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway

Fitzgerald, KA, McWhirter, SM, Faia, KL, Rowe, DC, Latz, E, Golenbock, DT, Coyle, AJ, Liao, SM, Maniatis, T

Nat Immunol 2003
23453971 Crystal structure and mechanism of activation of TANK-binding kinase 1

Larabi, A, Devos, JM, Ng, SL, Nanao, MH, Round, A, Maniatis, T, Panne, D

Cell Rep 2013
Participants
Participant Of
Orthologous Events
Authored
Reviewed
Created